Author:
Srinivasan Sahana,Kancheva Daliya,De Ren Sofie,Saito Takashi,Jans Maude,Boone Fleur,Vandendriessche Charysse,Paesmans Ine,Maurin Hervé,Vandenbroucke Roosmarijn E.,Hoste Esther,Voet Sofie,Scheyltjens Isabelle,Pavie Benjamin,Lippens Saskia,Schwabenland Marius,Prinz Marco,Saido Takaomi,Bottelbergs Astrid,Movahedi Kiavash,Lamkanfi Mohamed,van Loo Geert
Abstract
BackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disorder affecting memory and cognition. The disease is accompanied by an abnormal deposition of ß-amyloid plaques in the brain that contributes to neurodegeneration and is known to induce glial inflammation. Studies in the APP/PS1 mouse model of ß-amyloid-induced neuropathology have suggested a role for inflammasome activation in ß-amyloid-induced neuroinflammation and neuropathology.MethodsHere, we evaluated the in vivo role of microglia-selective and full body inflammasome signalling in several mouse models of ß-amyloid-induced AD neuropathology.ResultsMicroglia-specific deletion of the inflammasome regulator A20 and inflammasome effector protease caspase-1 in the AppNL-G-F and APP/PS1 models failed to identify a prominent role for microglial inflammasome signalling in ß-amyloid-induced neuropathology. Moreover, global inflammasome inactivation through respectively full body deletion of caspases 1 and 11 in AppNL-G-F mice and Nlrp3 deletion in APP/PS1 mice also failed to modulate amyloid pathology and disease progression. In agreement, single-cell RNA sequencing did not reveal an important role for Nlrp3 signalling in driving microglial activation and the transition into disease-associated states, both during homeostasis and upon amyloid pathology.ConclusionCollectively, these results question a generalizable role for inflammasome activation in preclinical amyloid-only models of neuroinflammation.
Subject
Immunology,Immunology and Allergy
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